Gut microbes play an important role in regulating host physiology and metabolism. Recent studies indicate that gut microbes affect memory formation and neurodegenerative disease manifestation. However, it is not fully understood how gut microbes influence gut?brain communication. The nematode C. elegans has a relatively simple nervous system and will readily ingest microbes from a petri dish. Therefore, C. elegans is a well-established model organism for studying the neural basis of behaviors and host?microbe interactions. By combining the two areas of research, we recently discovered that superoxide dismutase-1 (SOD-1), an enzyme that converts superoxide to less harmful peroxide, acts as a reactive sensor of reactive oxygen species in the nervous system and regulates the behavioral response to microbes. Our data indicate a previously unknown function of SOD-1 and suggest a potential role for SOD-1 in regulating microbe-induced gut?brain communication. In aim 1, we will determine how bacteria activate SOD-1. In aim 2, we will determine whether a neuropeptide functions as a signaling molecule between the gut and the nervous system to modulate the SOD-1 dependent response. In aim 3, we will define how SOD-1 and glutamatergic signaling regulate behavioral response to microbes. The proposed work will advance our knowledge in several ways. Our genetic model will open up a new research area for understanding the microbe-induced communication at the gut?brain axis. In addition, the proposed experiments will unveil new regulatory pathways of SOD-1. Our results may help to elucidate the underlying mechanisms of gut dysbiosis among elderly adults and patients with neurodegenerative diseases and may lead to the identification of potential therapeutic target.